Vaccines have traditionally been used to prevent infectious diseases. However, the ability of this drug to induce and amplify antigen-specific immune responses has long been considered a potentially valuable tool for cancer treatment. Early therapeutic vaccination strategies focus on abnormally expressed or overexpressed autoantigens in tumors, called tumor-associated antigens (TAA). However, this strategy is unsuccessful because TAA-specific T cells are affected by central and/or peripheral tolerance. In addition, these kinds of TAAs are also expressed to some extent in non-malignant tissues, which increases the risk of autoimmune toxicity induced by a vaccine.
Mutations in tumor cells can produce new autoantigen epitopes, called new epitopes or antigens. Vaccines based on new antigens rather than traditional TAAs have several advantages. First, only tumor cells express the new antigen, so it can trigger a real tumor-specific T cell response, thus preventing “off-target” damage to non-tumor tissues. Second, the new antigen is an epitope derived from somatic mutation, which may bypass the central tolerance of T cells to their epitopes and induce an immune response to a tumor. In addition, the new antigen-specific T cell response enhanced by these vaccines persists and provides the potential for immune memory after treatment, which provides the possibility for long-term prevention of disease recurrence.
Identification of New Immunogenic Antigens
To identify tumor-specific somatic mutations, researchers need to collect tumor biopsy and non-tumor tissue samples (usually peripheral blood mononuclear cells) from patients for exon sequencing of tumor and germline DNA. In addition, RNA sequencing provides information about the expression of mutant genes and further identification of mutations. The type of tumor can usually identify several tumor-specific mutations. However, not all mutations cause new epitopes to be recognized by the immune system due to the limitations of HLA. There are more than 16,000 well-known HLA-A, HLA-B, and HLA-C alleles, so it is necessary to consider HLA typing when predicting potential immunogen epitopes.
When adopting the computational method to predict the epitopes of CD8+T binding, the peptides with a strong affinity for HLA (IC50 < 150nmol/l) are more likely to induce MHC-I cell response. At present, various calculation methods for predicting MHC-I presentation epitopes have been developed, including using mass spectrometry to improve the prediction algorithm. However, the epitope prediction methods are mainly focused on MHC-I binding epitopes so far, and the more flexible binding epitopes of MHC-II make its epitope prediction more complex.
In addition to the calculation method, another way to induce the specific immune response of new antigens is to use tumor lysates. Autologous APCs, usually DCs, can be isolated from the patient, exposed to tumor lysates, and then injected back into the patient’s body to stimulate the immune response to TAAs or new antigens. This method avoids the sequencing and computational analysis needed to identify patient-specific new antigens. However, TAAs are unlikely to be immunogenic. In addition, the high abundance of non-immunogenic autoantigens may reduce the ability of related new epitopes to stimulate the immune response.
Quality of New Immunogenic Antigens
The success of the new antigen platform largely depends on the tumor mutation load (TMB). It is reasonable to assume that tumors with high TMB may have a corresponding number of new tumor antigens, which can target vaccines and better respond to ICI.
However, the occurrence of high TMB is not always consistent with the response of ICI. In addition to the inherent drug resistance mechanism of tumors, other reasons for this difference may be directly related to the “quality” of the new antigen, that is, the ability of the new antigen to produce a final TH1 cell and/or CTL response to the tumor.
The “quality” of the new antigen includes:
- The exogenous degree, that is, to measure the heterogeneity of the new antigen compared with the wild-type protein, the stronger the endogenous, the weaker the immunogenicity, and the easier it is to clear through immune tolerance.
- Most tumor cells express new antigens, while those with fewer distribution mutations are more likely to lose expression under the selection pressure of ICI.
- The mutation state of the tumor, compared with the passenger mutation, the driving mutation is less likely to escape.
- The affinity and expression of MHC-presenting molecules.
- The affinity of TCR and MHC complex.
Consideration of a New Antigen Vaccine Scheme
Many factors should be taken into account when designing therapeutic vaccination programs. After sample collection, the time required to generate a personalized vaccine is a vital factor, especially in metastatic disease environments. The time of production depends on the choice of vaccine platform. When designing and manufacturing custom vaccines, patients can benefit from combination therapy to cultivate a favorable immune environment. They can also accept adjuvant treatment before or after vaccination to enhance the immune response.
Other variables include the route of administration of the vaccine and any combination therapy, as well as the amount of enhanced vaccination. In the case of disease recurrence, researchers can repeat the tumor DNA sequencing and evaluate the vaccine-induced T cell response by blood and tumor samples to provide a basis for decision-making for follow-up treatment.
Challenge of New Antigen Vaccines
Although the preliminary clinical trial data of some new antigen vaccines showed strong immunogenicity and targeted tumor cell killing evidence, a relative proportion of the new epitopes of the vaccine did not stimulate T cell response. The primary challenge in cancer vaccine research is to improve our ability to induce T cell responses, especially the maximum activation and expansion of CD8+ T cells.
It is necessary to adopt complementary therapy to promote APC function and the optimal initiation of T cells in lymph nodes to achieve this goal. ICIs, costimulatory receptor agonists (such as CD40), TLR agonists, and growth factors supporting the development and/or function of DC (such as GM-CSF) and Fms-associated tyrosine kinase 3 ligands (FLT3L) are likely to achieve this.
Another challenge is identifying vaccine delivery systems so that vaccines can be produced quickly and cost-effectively so that they can be deployed promptly. Different forms of vaccines, including peptides, RNA, DNA, viral structure, or DC, have their advantages and disadvantages. However, there is a lack of head-to-head comparison of these different methods in patients.
The timing of ICI administration and therapeutic vaccination is another important consideration. It may be beneficial to combine ICIs with therapeutic vaccination regimens, but the most appropriate component treatment sequence needs to be carefully considered.